In age-related neurodegeneration, damaged proteins and organelles accumulate within neurons. Normally, these proteins and organelles would be degraded in the lysosomes by cathepsins, which are optimally active at acidic pH, but with aging, age-related diseases and lysosomal storage disorders, elevation of lysosomal pH hinders normal degradation and impairs autophagy leading to neuronal dysfunction. The molecular processes and signaling pathways that regulate lysosomal pH are not understood. While it has been shown that addition of exogenous cAMP can lower lysosomal pH, the relationship between cAMP and pH is unclear. Lysosomal pH is dependent upon the V-ATPase, and bicarbonate-regulated, soluble adenylyl cyclase (sAC) is essential for pH-dependent V-ATPase mobilization in both epididymis and kidney. We now show sAC to be essential for lysosomal acidification. In sAC null fibroblasts and primary neurons, lysosomal acidification is impaired resulting in diminished cathepsin activity, substrate proteolysis and autophagosome clearance during autophagy. The lysosomal acidification defect in sAC null cells is rescued by exogenous cAMP. Thus, sAC appears to be an essential source of cAMP which regulates lysosomal pH. These results suggest sAC serves as a previously unappreciated sensor of lysosomal pH, and define it as a possible target for designing novel treatment strategies for neurodegenerative disorders.